d-jnki-1 and Hearing-Loss--Sensorineural

There is a growing interest in the auditory community to develop novel prophylactic and therapeutic drugs to prevent permanent sensorineural hearing loss following acute cochlear injury. The jun-N-terminal protein kinase (JNK) pathway plays a crucial role in acute sensory hearing loss. Blocking the JNK pathway using the cell-penetrating peptide D-JNKI-1 (AM-111/brimapitide) has shown promise as both a prophylactic and therapeutic agent for acute cochlear injury. A number of pre-clinical and clinical studies have determined the impact of D-JNKI-1 on acute sensorineural hearing loss. Given the inner-ear selective therapeutic profile, local route of administration, and ability to diffuse across cellular membranes rapidly using both active and passive transport makes D-JNK-1 a promising oto-protective drug. In this review article, we discuss the application of D-JNKI-1 in various auditory disorders as well as its pharmacological properties and distribution in the cochlea.

Topics: Animals; Cell Membrane Permeability; Cell-Penetrating Peptides; Cochlea; Cochlear Diseases; Cytoprotection; Enzyme Inhibitors; Hearing; Hearing Loss, Sensorineural; Humans; JNK Mitogen-Activated Protein Kinases; Peptides; Prognosis; Risk Factors; Signal Transduction

To confirm the efficacy and safety of AM-111 (brimapitide), a cell-penetrating c-Jun N-terminal Kinase (JNK) inhibitor, in patients suffering from severe to profound acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL).. Prospective, double-blind, randomized, placebo-controlled phase 3 study with follow-up visits on Days 3, 7, 28, and 91.. Fifty-one European and Asian sites (tertiary referral centers, private ENT practices).. Two hundred fifty-six patients aged 18 to 65 years presenting within 72 hours following ISSNHL onset with mean hearing loss ≥ 40 dB and mean threshold ≥ 60 dB at the 3 worst affected contiguous test frequencies.. Single-dose intratympanic injection of AM-111 (0.4 or 0.8 mg/ml) or placebo; oral prednisolone as reserve therapy if hearing improvement < 10 dB at Day 7.. Hearing improvement to Day 28 was the primary efficacy endpoint; complete hearing recovery, frequency of reserve therapy used, complete tinnitus remission, improvement in word recognition were secondary endpoints. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events.. While the primary efficacy endpoint was not met in the overall study population, post-hoc analysis showed a clinically relevant and nominally significant treatment effect for AM-111 0.4 mg/ml in patients with profound ISSNHL. The study drug and the administration procedure were well tolerated.. AM-111 provides effective otoprotection in case of profound ISSNHL. Activation of the JNK stress kinase, AM-111's pharmacologic target, seems to set in only following pronounced acute cochlear injury associated with large hearing threshold shifts.

Topics: Adult; Aged; Double-Blind Method; Female; Hearing Loss, Sensorineural; Hearing Loss, Sudden; Hearing Loss, Unilateral; Humans; Injection, Intratympanic; Male; Middle Aged; Peptides; Prospective Studies; Treatment Outcome; Young Adult

To evaluate the efficacy and safety of AM-111, a c-Jun N-terminal Kinase (JNK) ligand, in patients with acute sensorineural hearing loss (ASNHL).. Prospective, double-blind, randomized, placebo-controlled study with follow-up visits on Days 3, 7, 30, and 90.. Twenty-five European sites (academic tertiary referral centers, private ENT practices).. Approximately 210 patients aged 18 to 61 years presenting within 48 hours after acute acoustic trauma or idiopathic sudden sensorineural hearing loss with mean hearing loss of 30 dB or greater at the 3 most affected contiguous test frequencies.. Single-dose intratympanic injection of AM-111 (0.4 or 2.0 mg/ml) or placebo; optionally, oral prednisolone if hearing improvement was less than 10 dB at Day 7.. Efficacy was assessed by absolute hearing improvement (primary end point, Day 7), percentage hearing improvement, complete hearing recovery, speech discrimination improvement, and complete tinnitus remission. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events.. The study failed to demonstrate a treatment benefit for the entire study population because mild-to-moderate ASNHL cases showed unexpectedly strong spontaneous recovery. In severe-to-profound ASNHL patients (threshold ≥60 dB), AM-111 0.4 mg/ml showed statistically significant, clinically relevant, and persistent improvements in hearing and speech discrimination and higher tinnitus remission compared with placebo. The study drug and the intratympanic injections were well tolerated.. The study established proof of concept for AM-111 in the treatment of severe-to-profound ASNHL. Control for spontaneous hearing recovery is essential for ASNHL studies.

Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hearing Loss, Sensorineural; Hearing Loss, Sudden; Humans; Male; Middle Aged; Neuroprotective Agents; Peptides; Prospective Studies; Tinnitus; Treatment Outcome; Tympanic Membrane; Young Adult